A small molecule p75NTR ligand prevents cognitive deficits and neurite degeneration in an Alzheimer's mouse model

• Published in: Neurobiology of aging Vol. 34; no. 8; pp. 2052 - 2063
• Main Authors: Knowles, Juliet K, Simmons, Danielle A, Nguyen, Thuy-Vi V, Vander Griend, Lilith, Xie, Youmei, Zhang, Hong, Yang, Tao, Pollak, Julia, Chang, Timothy, Arancio, Ottavio, Buckwalter, Marion S, Wyss-Coray, Tony, Massa, Stephen M, Longo, Frank M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2013
• Subjects: Administration, Oral; Aging; Alzheimer Disease - drug therapy; Alzheimer Disease - pathology; Alzheimers' disease; Amyloid beta-Peptides - metabolism; Animals; Brain - metabolism; Brain - pathology; Cognition Disorders - prevention & control; Disease Models, Animal; Female; Internal Medicine; Isoleucine - administration & dosage; Isoleucine - analogs & derivatives; Isoleucine - pharmacology; Isoleucine - therapeutic use; Ligands; LM11A-31; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Molecular Targeted Therapy; Morpholines - administration & dosage; Morpholines - pharmacology; Morpholines - therapeutic use; Nerve Degeneration - prevention & control; Neurites - pathology; Neuritic dystrophy; Neurology; p75 neurotrophin receptor; Receptors, Nerve Growth Factor - physiology; Alzheimers' disease; Neuritic dystrophy; LM11A-31; p75 neurotrophin receptor
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2013.02.015

Abstract The p75 neurotrophin receptor (p75NTR ) is associated with multiple mechanisms linked to Alzheimer's disease (AD); hence, modulating its function might confer therapeutic effects. In previous in vitro work, we developed small molecule p75NTR ligands that inhibited amyloid-β-induced degenerative signaling and prevented neurite degeneration. In the present study, a prototype p75NTR ligand, LM11A-31, was administered orally to the Thy-1 hAPPLond/Swe (APPL/S ) AD mouse model. LM11A-31 reached brain concentrations known to inhibit degenerative signaling without toxicity or induction of hyperalgesia. It prevented deficits in novel object recognition after 2.5 months and, in a separate cohort, deficits in Y-maze performance after 3 months of treatment. Stereology studies found that the number and size of basal forebrain cholinergic neurons, which are normal in APPL/S mice, were unaffected. Neuritic dystrophy, however, was readily apparent in the basal forebrain, hippocampus and cortex, and was significantly reduced by LM11A-31, with no effect on amyloid levels. These studies reveal that p75NTR is an important and tractable in vivo drug target for AD, with LM11A-31 representing a novel class of therapeutic candidates.